24 MOLEKÜLDESIGN: VOM MOLEKÜL ZUM PATIENTEN 1.1 Ribozymes for drug screening Michael Famulok Being able to rapidly identify interaction partners of target proteins with novel, general applicable assay approaches is a major goal of modern biomolecular research and drug discovery. We have developed a modular assay system which allows us to screen for novel lead structures for a given protein target, as also to detect proteinprotein interactions. Protein-dependent reporter ribozymes change their catalytic activity in the presence of its cognate protein. Upon addition of an interaction partner altering the function of the protein, the catalytic activity switches back and senses the molecular interaction. Examples of sensitive and highly specific detection of interactions between biomacromolecules or novel interactions between a protein and a small molecule, compatible with High-Throughput-Screening conditions, are provided. This highly modular approach is generalizable, independent of target protein function, does not require labeling of proteins or library members and is best suited for high-throughput applications due to its non-radioactive, fluorescence readout within minutes. Prof. Dr. Michael Famulok University of Bonn Faculty of Medicine Kekulé-Institute of Organic Chemistry and Biochemistry 24

26 MOLEKÜLDESIGN: VOM MOLEKÜL ZUM PATIENTEN 1.3 Targeting the cyclic ADP-ribose signaling pathway in inflammation and immunity Andreas H. Guse Stimulation of T-lymphocytes via the T cell receptor/cd3 complex (TCR/CD3) activates a multitude of intracellular signaling pathways. Among these, Ca 2+ signaling is one of the essential events involving Ca 2+ release by intracellular second messengers, but also Ca 2+ entry via the plasma membrane 1. In the last years we have demonstrated the involvement of D-myo-inositol 1,4,5-trisphosphate (IP 3 ), cyclic ADP-ribose (cadpr) and nicotinic acid adenine dinucleotide phosphate as Ca 2+ releasing intracellular messengers 2,3. Modulation of T cell Ca 2+ signaling may be used to therapeutically intervene with T cell activation, and thus with activation of immune responses. The cadpr/ca 2+ signaling pathway starts by synthesis of cadpr from ß-NAD by ADP-ribosyl cyclase (ADPRC). This enzyme, though not yet molecularly identified, thereby constitutes one of the potential targets. Several substrate analogues have been analysed for their inhibitory properties of ADPRC. Derivatives of both ß-NAD and NHD (nicotinamide hypoxanthine dinucleotide) inhibited ADPRC. Membrane-permeant analogues of these inhibitors decreased TCR/CD3 mediated Ca 2+ signalling and proliferation of T cells. A second potential target is the receptor protein for cadpr. The prime candidate for a cadpr receptor is the Ca 2+ channel responding to cadpr, the ryanodine receptor (RyR); however, an additional cadpr-binding protein cannot be excluded at present. Several cadpr analogues have been analysed to gain insight into the structure-activity relationship. Membrane-permeant cadpr antagonists effectively inhibited T cell activation, analysed as suppression of Ca 2+ signaling, activation antigen expression and proliferation. 26

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